Novel antibacterial compounds specifically targeting the essential WalR response regulator

Yasuhiro Gotoh, Akihiro Doi, Eiji Furuta, Sarah Dubrac, Yoshimasa Ishizaki, Masato Okada, Masayuki Igarashi, Norihiko Misawa, Hirofumi Yoshikawa, Toshihide Okajima, Tarek Msadek, Ryutaro Utsumi

Research output: Contribution to journalArticlepeer-review

44 Citations (Scopus)


The WalK/WalR (YycG/YycF) two-component system, which is essential for cell viability, is highly conserved and specific to low-GC percentage of Gram-positive bacteria, making it an attractive target for novel antimicrobial compounds. Recent work has shown that WalK/WalR exerts an effect as a master regulatory system in controlling and coordinating cell wall metabolism with cell division in Bacillus subtilis and Staphylococcus aureus. In this paper, we develop a high-throughput screening system for WalR inhibitors and identify two novel inhibitors targeting the WalR response regulator (RR): walrycin A (4-methoxy-1-naphthol) and walrycin B (1,6-dimethyl-3-4-(trifluoromethyl) phenylpyrimido5,4-e1,2,4triazine-5,7-dione). Addition of these compounds simultaneously affects the expression of WalR regulon genes, leading to phenotypes consistent with those of cells starved for the WalK/WalR system and having a bactericidal effect. B. subtilis cells form extremely long aseptate filaments and S. aureus cells form large aggregates under these conditions. These results show that walrycins A and B are the first antibacterial agents targeting WalR in B. subtilis and S. aureus.

Original languageEnglish
Pages (from-to)127-134
Number of pages8
JournalJournal of Antibiotics
Issue number3
Publication statusPublished - Mar 2010
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Drug Discovery


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